Exportin 1 (XPO1) is aberrantly overexpressed in various malignant tumors and can lead to the loss of anti-tumor effects of important tumor suppressor proteins such as p53, RB1, and FOXO by mediating their nuclear export. Although XPO1 inhibitor Selinexor has entered clinical application, its single-agent anti-tumor activity remains suboptimal, which is closely related to the compensatory activation of multiple signaling pathways in response to XPO1 inhibition. Focusing on the core regulatory role of XPO1 in tumor cells, this article systematically summarizes the current landscape of combination therapies involving XPO1 inhibitors and various targeted agents, including inhibitors of CDK4/6, FLT3, BET, ATR, and BCL2/MDM2, aiming to provide some reference for the development of XPO1-centered combination therapy strategies.

Objective To develop albumin-binding indocyanine green (ICG) and assess its potential for near-infrared fluorescence imaging and intraoperative navigation in lung cancer. Methods ABD-tri was recombinantly expressed by genetic engineering. Its albumin-binding capability was determined using size-exclusion chromatography, and its albumin-dependent binding to lung cancer cells was evaluated by flow cytometry. ICG was conjugated to ABD-tri to generate the fluorescent probe ABD-tri-ICG. The potential of ABD-tri-ICG for near-infrared fluorescence imaging and imaging-guided tumor resection was evaluated in mice bearing subcutaneous tumor grafts of lung cancer. Results ABD-tri was highly expressed in Escherichia coli (E. coli) and was purified to homogeneity via a simple affinity chromatography. ABD-tri bound both human and murine serum albumin, contributing to its binding to lung cancer cells. ICG was effectively conjugated to ABD-tri to produce the fluorescence probe ABD-tri-ICG after mixing and incubation at room temperature for 1 h. In mice bearing lung cancer tumor grafts, intravenously injected ABD-tri-ICG enabled clear visualization of tumors with diameters ranging from 5 to 7 mm within 0.5-24 h post-injection. The tumor grafts were resected under the guidance of ABD-tri-ICG-mediated near-infrared fluorescence imaging. Conclusion Intravenous injection of ABD-tri-ICG allows rapid and sustained visualization of lung cancer tumor grafts and enables intraoperative navigation in mice, warranting further evaluation on the clinical translation of ABD-tri-ICG.

Laboratory animal science is an emerging interdisciplinary field supporting life science and medical research, and a key component of talent cultivation and technological innovation in medical colleges. Currently, this field faces challenges such as a significant imbalance between talent supply and demand and a weak systematic training system. To respond to national strategies and societal needs, Shandong First Medical University established the School of Laboratory Animal through industry-education integration during the 14th Five-Year Plan period. The school is based on The Medical Laboratory Technology major, cultivates application-oriented, interdisciplinary professionals in laboratory animal science, and has constructed a three-in-one training system integrating "course learning–scientific research–industry practice". Specific measures for talent cultivation include: optimizing the general education, professional courses, and intensive practical modules in the talent training program, and establishing the "Yellow River Class" integrating industry and education; implementing an undergraduate mentor system, and conducting scientific research training based on The Model Animal Research and Development Engineering Laboratory; collaborating with bases across the entire industrial chain of laboratory animal production, research, application, and quality control, appointing industry mentors, and strengthening practical teaching. Practice has shown that this system has been remarkably effective: a total of 320 undergraduate students have been enrolled since 2020; the employment rate of undergraduate graduates for two consecutive cohorts has reached 100%, and the postgraduate enrollment rate has exceeded 50%; undergraduate students have won numerous national and provincial awards in academic competitions, and have obtained multiple patents and published papers. In the future, the school will further integrate the advantages of medicine, agriculture, and science, optimize the depth and breadth of courses, strengthen the construction of faculty and teaching materials, and improve the undergraduate-master's integrated training mechanism. This article can provide a reference for the training of professionals in laboratory animal science and related biomedical fields in medical colleges.

Plant-derived extracellular vesicles (PDEVs) are nanoscale extracellular vesicles secreted by plant cells, characterized by a lipid bilayer structure. These vesicles carry a variety of bioactive molecules, including proteins, nucleic acids, and lipids, and play essential roles in intercellular communication and physiological regulation in plants. Compared to animal-derived extracellular vesicles, PDEVs offer several advantages, such as a broad range of sources, high biocompatibility, low immunogenicity, and low production costs. Furthermore, PDEVs have demonstrated remarkable potential as natural nanocarriers for drug delivery, due to their ability to efficiently traverse biological barriers, such as the blood-brain barrier, making them promising candidates for drug delivery systems. This review systematically elaborates on the complex composition of PDEVs, which consists of lipids, proteins, and nucleic acids, the typical structural characteristics of their lipid bilayers ranging from 30 to 150 nm, and their versatile loading capabilities as drug carriers, efficiently encapsulating various types of therapeutic agents such as hydrophilic small molecules, hydrophobic drugs, nucleic acids, and proteins. We systematically summarize the recent advancements in strategies for enhancing the loading efficiency of PDEVs, which include methods such as co-incubation, ultrasound-assisted loading, electroporation, freeze-thaw cycles, and microfluidic technology. These techniques are evaluated based on their underlying principles, suitable drug types, and their respective advantages. In addition to loading strategies, we focus on the engineered approaches to achieve targeted delivery using PDEVs, such as genetic engineering modifications, chemical ligand conjugation, membrane fusion technology, and polyethylene glycol (PEG) modification. We discuss the mechanisms of these strategies in enhancing targeting efficiency, prolonging in vivo circulation time, and improving therapeutic efficacy. Further, this review highlights the application of PDEVs in various disease models, including tumor, skin inflammation, metabolic disorders, and neurodegenerative diseases, showcasing their therapeutic potential as multifunctional delivery platforms. The ability of PDEVs to encapsulate diverse therapeutic agents and target specific tissues or cells opens up new avenues for the treatment of complex diseases, offering advantages over conventional drug delivery systems. However, despite the promising applications of PDEVs, several challenges remain in their development and clinical translation. These challenges include variability in source materials, standardization of preparation processes, quality control, scalability of production, and the need for clinical validation. To overcome these obstacles, the integration of advanced technologies such as artificial intelligence-assisted design and multi-omics analysis is proposed as a way to facilitate the precise development of PDEVs. These emerging technologies hold the potential to further enhance the precision and effectiveness of plant-based drug delivery systems, ultimately advancing the field of precision medicine. In conclusion, the use of PDEVs as a platform for drug delivery represents a promising area of research with the potential to revolutionize therapeutic strategies. Their ability to encapsulate and deliver a wide variety of bioactive molecules, along with their inherent advantages in biocompatibility and versatility, makes them a valuable tool in the development of more efficient and targeted therapeutic interventions. Continued research and innovation in this field will pave the way for the clinical implementation of PDEVs in the treatment of various diseases, offering new hope for more effective and sustainable therapeutic options.

OBJECTIVE To investigate the ameliorative effects of Imperatae Rhizoma （RI） extract against doxorubicin （DOX）-induced myocardial injury and its potential molecular mechanisms. METHODS Network pharmacology was employed to screen for target overlap between the predicted core targets of RI’s active components and targets associated with myocardial injury， followed by gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analyses. Based on the network pharmacology results， a DOX-induced myocardial injury mouse model was established using male C57BL/6J mice to observe the effects of RI extract [1 g/（kg·d）] on the survival rate， body weight， and cardiac damage. A DOX-injured HL-1 cardiomyocyte model was established to assess the effects of different mass concentrations of RI extract （50， 100， 200 μg/mL） on mitochondrial membrane potential， adenosine triphosphate （ATP） production， reactive oxygen species （ROS） generation， apoptosis， and expression of the relevant target proteins. The mechanism was validated by transfecting with small interfering RNA of estrogen receptor 1 （ESR1）. RESULTS A total of 58 overlapping targets were screened， which were enriched in biological processes such as hormone response and hypoxia response， as well as pathways including apoptosis， tricarboxylic acid cycle， and pyruvate metabolism. Key target proteins， such as ESR1， were also identified. Animal experiments confirmed that the survival rate of mice in the DOX+RI group was obviously higher than that in the DOX group， with a slower rate of weight loss and improved pathological changes， such as cardiac atrophy and inflammatory cell infiltration， compared to the DOX group. Cell experiments showed that， compared with the DOX group， the DOX+RI groups exhibited significantly increased or upregulated mitochondrial membrane potential， relative ATP levels， and mRNA expressions of isocitrate dehydrogenase 3A （IDH3A）， succinate dehydrogenase A （SDHA） and peroxisome proliferators-activated receptor γ coactivator-1α （PGC-1α）， as well as mRNA and protein expressions of ESR1； conversely， relative ROS levels and apoptosis rates were significantly reduced （ P ＜0.05）. Following ESR1 knockdown， the anti-apoptotic effect of the RI extract on cardiomyocytes was significantly attenuated （ P ＜0.05）. CONCLUSIONS The RI extract may alleviate DOX-induced myocardial injury by activating the ESR1 signaling pathway， improving mitochondrial function， and inhibiting excessive ROS production and cardiomyocyte apoptosis.

Intervertebral disc degeneration (IVDD) is the predominant pathological contributor to chronic low back pain, a pervasive musculoskeletal condition affecting over 630 million people globally and imposing tremendous socioeconomic and public health burdens. The etiopathogenesis of IVDD is remarkably complex and multifactorial, involving intricate crosstalk among chronic inflammatory responses, extracellular matrix (ECM) catabolism, cellular senescence, aberrant programmed cell death (including apoptosis, pyroptosis, and ferroptosis), mitochondrial dysfunction, and oxidative damage. Compelling evidence indicates that the inflammatory microenvironment acts as a decisive driving force throughout the entire degenerative course of IVDD. Among the diverse inflammatory mediators, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) serve as core pro-inflammatory cytokines that initiate and perpetuate the degenerative cascade. These two pivotal cytokines collectively activate an array of canonical intracellular signaling pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome, and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) cascade. Such interconnected signaling networks trigger a self-reinforcing positive feedback loop, which exacerbates inflammatory reactions, disrupts the anabolic-catabolic homeostasis of the ECM, promotes oxidative stress and mitochondrial injury, induces multiple forms of disc cell death, and ultimately leads to progressive structural collapse and functional deterioration of the intervertebral disc. Conventional therapeutic strategies, dominated by nonsteroidal anti-inflammatory drugs and surgical interventions, are limited by systemic adverse reactions, suboptimal long-term efficacy, and the risk of adjacent segment degeneration. In contrast, traditional Chinese medicine (TCM) exhibits prominent advantages in the prevention and treatment of IVDD by virtue of its holistic regulation, syndrome differentiation, and multi-component, multi-target, multi-pathway pharmacological properties. This review systematically elucidates the molecular mechanisms by which inflammation-associated signaling pathways modulate disc cell fate and ECM metabolic homeostasis, and comprehensively summarizes the experimental progress over the past five years on TCM monomers and compound formulas for intervening in IVDD. Accumulating studies have confirmed that numerous natural active ingredients isolated from herbal medicines (ferulic acid, mangiferin, paeonol, astragaloside IV) and representative TCM compound prescriptions (Bushen Huoxue Formula, Shensuitongzhi Formula, Fuzi Decoction) exert synergistic protective effects by coordinately targeting core signaling hubs. These TCM agents demonstrate potent anti-inflammatory, antioxidant, anti-apoptotic, anti-pyroptotic, anti-ferroptotic, ECM-protective, and autophagy-regulating bioactivities, thereby effectively decelerating the pathological progression of IVDD. Despite remarkable progress, current investigations are still confronted by several critical limitations. Most studies are restricted to validating the regulatory effects of single TCM components on individual signaling pathways, leaving the systematic, dynamic, and synergistic mechanisms of TCM compound formulas within multi-pathway regulatory networks largely unexplored. Furthermore, clinical translation of TCM is severely hampered by the lack of efficient targeted drug delivery systems, unclear pharmacokinetic profiles, suboptimal local bioavailability, and incomplete long-term safety assessments. Therefore, future research should adopt an interdisciplinary paradigm integrating multi-omics technologies, artificial intelligence, organoid models, and organ-on-chip systems to systematically decipher the scientific basis of TCM against IVDD. Concurrently, the development of intelligent, site-specific delivery systems (hydrogels, nanoparticles, exosome-based carriers) is urgently needed to enhance the local accumulation and sustained release of TCM ingredients. By deepening mechanistic exploration and accelerating translational research, TCM is expected to evolve into safe, effective, and personalized precision therapeutic regimens for IVDD, offering novel and reliable solutions for the clinical management of chronic low back pain.

The initiation of adaptive immune responses relies on the precise recognition and interpretation of antigenic information. In this process, the specific binding of T cell receptors (TCRs) to peptide-major histocompatibility complex (pMHC) molecules represents one of the key molecular events in the initiation of adaptive immune responses. Accordingly, the structural features of TCR-pMHC complexes provide a fundamental basis for dissecting antigen recognition mechanisms and support rational vaccine design, therapeutic target discovery in TCR-based immunotherapy, and TCR identification and optimization. However, experimental determination of TCR-pMHC structures remains costly, time-consuming, and limited in coverage, making computational approaches essential for rapidly obtaining reliable structural information. Computational methods for predicting the structures of TCR-pMHC complexes have advanced rapidly in recent years, driven by progress in deep learning-based modeling frameworks and the increasing availability of structural and sequence resources. Despite these developments, most existing tools do not adequately distinguish the key structural and biophysical differences between MHC class I (MHC-I) and MHC class II (MHC-II) complexes during model construction. As a consequence, their predictive performance differs substantially between class I and class II complexes. In general, structural predictions for class I complexes outperform those for class II complexes. This discrepancy may be related to several fundamental differences between the two systems, including the architecture of the peptide-binding groove, the distribution of peptide lengths, and the properties of peptide flanking residues (PFRs). Compared with MHC-I molecules, MHC-II molecules usually bind longer antigenic peptides, which typically range from 13 to 25 amino acids in length. PFRs at both termini of these peptides participate in regulating the overall conformation of TCR-pMHC class II complexes and exert a pronounced effect on the geometric and physicochemical characteristics of the TCR-pMHC binding interface. Furthermore, within the TCR recognition interface, the complementarity-determining regions (CDRs) consist of segments that differ markedly in conformational behavior. They commonly include regions that are relatively rigid and structurally stable, together with highly flexible segments exhibiting substantial conformational plasticity. These rigidity-flexibility features constitute an essential structural basis enabling TCRs to recognize diverse peptide-MHC ligands and to accommodate conformational heterogeneity at the interface. However, many current modeling tools, in an effort to enforce global conformational stability or reduce structural noise, tend to over-constrain intrinsically flexible regions. Such oversimplification may lead to inappropriate rigidification of flexible CDR loops, resulting in local structural distortions, compromised interface geometry, or even complete modeling failure for specific complexes. Against this background, the review approaches the field from the perspective of computational differences between MHC-I and MHC-II complexes. We first systematically organize and summarize available resources related to TCRs and pMHCs, including structural datasets, sequence databases, prediction tools, and benchmarking studies. We then focus on five representative tools capable of predicting both class I and class II complexes—AlphaFold2, AlphaFold3, TCRmodel2, tFold-TCR, and TCR-pHLA_ModellerS. After excluding structures present in the training sets of these tools, we constructed a benchmark dataset comprising 25 class I and 10 class II TCR-pMHC complexes in the bound state and conducted a systematic evaluation using this dataset. We first employ widely used general evaluation metrics, including All-Atom Root Mean Square Deviation (All-Atom RMSD), Backbone RMSD, Template Modeling score (TM-score), and DockQ, to assess the global conformational accuracy and interface modeling quality of class I and class II complexes. For class II complexes, we propose for the first time a peptide flanking residue deviation index, including the PFRs-Deviation Index (PFRs-DI), N-PFR-Deviation Index (N-PFR-DI), and C-PFR-Deviation Index (C-PFR-DI), to quantitatively characterize conformational deviations in PFRs. In addition, we propose the CDR conformational consistency index (CCC) designed to qualitatively evaluate the ability of prediction tools to capture TCR CDR conformational flexibility. These metrics collectively assess a tool’s ability to model both overall conformation and critical functional regions, thereby addressing the limitations of existing evaluation criteria that overemphasize global structure while inadequately capturing modeling quality in key functional areas. This establishes a unified analytical framework for MHC-I and MHC-II complexes to guide data resource selection, modeling strategy formulation, and evaluation system development. The framework further advances computational modeling and provides crucial support for multi-scale analysis of TCR-pMHC recognition mechanisms and their biological functions.

ObjectiveTo explore the feasibility of constructing a programmed death receptor-1（PD-1） molecular probe for non-invasive micro-positron emission tomography/computed tomography （Micro-PET/CT） imaging of PD-1 protein in mouse S180 sarcoma. MethodsA transgenic PD-1 C57 S180 sarcoma mouse model was established using the S180 sarcoma cell injection. Furthermore， ¹²⁴I-anti-PD-1 monoclonal antibody probe was synthesized. 18.5 MBq of the ¹²⁴I-anti-PD-1 probe was injected into the tail vein of transgenic PD-1 C57 mice. Subsequently， S180 sarcoma was imaged using Micro-PET/CT. ResultsStudy successfully established a transgenic PD-1 C57 S180 sarcoma mouse model. Immunohistochemical （IHC） results showed PD-1 protein expression in S180 sarcoma. Micro-PET/CT imaging successfully visualized the PD-1 protein receptor in S180 sarcoma at different time points （20， 48， 72， and 120 h） after probe injection. ConclusionThe ¹²⁴I-anti-PD-1 monoclonal antibody molecular probe successfully targets the PD-1 receptor in S180 sarcoma of transgenic PD-1 C57 mice， and presents clear Micro-PET/CT immunoassay results， thus it potentially enables the non-invasive screening of patients with PD-1 positive malignant tumors.

BACKGROUND:Acupuncture at Xinshu(BL 15)can significantly improve cardiac function and protect myocardial cells in acute myocardial ischemia,but the effect and mechanism of thread embedding treatment at Xinshu(BL 15)on cardiac function in acute myocardial ischemia are yet unclear.Nuclear factor κB activation often appears as an intranuclear translocation of the P65 isoform,and activation of the nuclear factor κB signaling pathway is marked by elevated P65 levels.OBJECTIVE:To explore the effects of thread embedding pretreatment at Xinshu(BL 15)on cardiac function and the expression levels of interleukin-10,tumor necrosis factor-α,P65 genes and proteins in rats with acute myocardial ischemia.METHODS:Thirty-two male Sprague-Dawley rats were randomly divided into a blank group,a model group,a Xinshu(BL 15)acupoint group,and a non-meridian/non-acupoint group using a random number table method,with eight rats in each group.Rat models of acute myocardial ischemia were established in the latter three groups.The Xinshu(BL 15)acupoint group had thread embedding at Xinshu(BL 15)for 14 days,followed by subcutaneous injection of isoproterenol hydrochloride into the back to establish an acute myocardial ischemia rat model.The non-meridian/non-acupoint group had local thread embedding for 14 days,and the rest procedures were the same as above.In the model group,Xinshu(BL 15)was only marked,and the rest procedures were the same as above.In the blank group,Xinshu(BL 15)was only marked,and then an equal amount of physiological saline was injected subcutaneously into the back.After 24 hours of modeling,electrocardiogram and cardiac ultrasound were performed.Abdominal aorta blood was extracted for detection of serum creatine kinase and creatine kinase isoenzyme levels using enzyme-linked immunosorbent assay.Subsequently,the rats were euthanized and samples were collected.Hematoxylin-eosin and TUNEL staining were used to observe the pathological changes of myocardial tissue and the apoptosis of myocardial cells.Real-time fluorescence quantitative PCR(RT-qPCR)and western blot were used to detect the mRNA and protein expression of tumor necrosis factor-α,interleukin-10,and P65 in myocardial tissue respectively.RESULTS AND CONCLUSION:(1)Electrocardiogram:Compared with the blank group,the model group,non-meridian/non-acupoint group,and Xinshu(BL 15)acupoint group had significantly elevated ST segment in lead Ⅱ of the electrocardiogram.(2)Cardiac ultrasound:Compared with the model group,the Left ventricular end-systolic dimension in the Xinshu(BL 15)acupoint group were significantly reduced(P＜0.05),while left ventricular ejection fraction and left ventricular fractional shortening rate were significantly increased(P＜0.05).(4)Serum creatine kinase and creatine kinase isoenzyme:Compared with the model group,the Xinshu(BL 15)acupoint group showed a significant decrease in serum creatine kinase and creatine kinase isoenzyme levels(P＜0.05).(4)Hematoxylin-eosin staining:Compared with the model group,the arrangement of myocardial fibers in the Xinshu(BL 15)acupoint group was basically neat,with less edema and a small amount of inflammatory cell infiltration.(5)TUNEL staining:Compared with the model group,the fluorescence intensity of myocardial cell apoptosis in the Xinshu(BL 15)acupoint group was significantly reduced,and its apoptosis rate was significantly reduced(P＜0.05).(6)RT-qPCR and western blot:Compared with the model group,the myocardial tissue interleukin-10 level in the Xinshu(BL 15)acupoint group was significantly increased(P＜0.05),while tumor necrosis factor-α and P65 levels were significantly decreased(P＜0.05).These findings indicate that thread embedding pretreatment at Xinshu(BL 15)can improve cardiac function in rats with acute myocardial ischemia,and its mechanism of action may be related to the inhibition of the activation of the nuclear factor-κB signaling pathway.

OBJECTIVE To evaluate the cost-effectiveness of anlotinib combined with penpulimab versus sorafenib as first- line treatment for unresectable hepatocellular carcinoma （uHCC） from the perspective of China’s healthcare system. METHODS Based on data from the APOLLO study， a partitioned survival model was established with a 21-day model cycle to simulate patient survival status over 10 years under anlotinib combined with penpulimab regimen or sorafenib monotherapy. Quality-adjusted life year （QALY） was used as the core evaluation parameter to assess the incremental cost-effectiveness ratio （ICER） of different treatment regimens. Using 3 times China’s per capita gross domestic product （GDP） in 2024 （287 247 yuan/QALY） as the willingness-to-pay （WTP） threshold， cost-utility analysis was performed to evaluate the cost-effectiveness of the treatment regimens. Sensitivity analysis was conducted to validate the robustness of the baseline analysis conclusion. Scenario analysis was performed to consider the impact of anlotinib and penpulimab assistance programs on the results； the price reduction of penpulimab to ensure the cost-effectiveness of the combination regimen was examined under varying WTP thresholds （specifically， 1， 2， and 3 times China’s per capita GDP in 2024）. RESULTS The baseline analysis revealed that the ICER of anlotinib combined with penpulimab regimen relative to the sorafenib regimen was 338 611.20 yuan/QALY， which exceeded the WTP threshold set in this study. Univariate sensitivity analysis indicated that the utility value of progression free survival and penpulimab price significantly influenced the baseline analysis results. Probabilistic sensitivity analysis validated the robustness of the baseline results. The results of scenario analysis indicated that when considering the assistance programs for anlotinib and penpulimab， the obtained ICER values were all below the WTP threshold set at 3 times China’s per capita GDP in 2024. When the price of penpulimab was reduced by 58%， 35%， and 13%， the ICER values were below the WTP threshold， which was 1， 2 and 3 times the per capita GDP of China in 2024， respectively. CONCLUSIONS From the perspective of China’s healthcare system， anlotinib combined with penpulimab regimen for first-line treatment of uHCC lacks cost-effectiveness compared to sorafenib regimen. However， this conclusion would be reversed if the anlotinib and penpulimab assistance programs are taken into account or if the price of penpulimab is reduced by more than 13% and above.